Renal progenitor biology proffers valuable insight into the prevention and treatment of congenital kidney defects, which are among the leading causes of chronic renal failure in children. Much is known about the events that trigger the initial stages of kidney formation from gene targeting studies in mice. However, due to the complex nature of mammalian kidney development, there is a paucity of knowledge regarding how renal progenitors form mature nephrons-the fundamental units of the kidney that are made up of a series of discrete functional segments. The zebrafish model system provides a unique opportunity to discover how nephron segmentation occurs. Zebrafish embryos form an anatomically simple kidney of just two nephrons, which were recently shown to possess a segment organization akin to mammals. The zebrafish model is advantageous for loss- and gain-of-function genetic studies in renal progenitors due to the external fertilization and transparency of embryos, combined with the powerful molecular tools now available in this system. We propose to further characterize the nephron segment alterations in the retinoic acid (RA) deficient mutant, light bulb, and to determine the mechanisms by which renal progenitors respond to RA signaling during early stages of nephrogenesis. In addition, we will assign the roles and interrelationships between the Irx3b and Evi1 transcription factors in subsequent events of segment formation. The overall goal of this K01 application is to use the advantages of the zebrafish model to delineate the genetic pathways that direct nephron maturation by building a hierarchy of the pathways responsible for renal progenitor specification. This award will provide the candidate, Dr. Rebecca Wingert, a period of mentored research training in the laboratory of Dr. Alan Davidson, an experienced zebrafish biologist and emerging leader in nephrology. This training is essential for Dr. Wingert to develop the repertoire of skills to achieve her goal of becoming a successful, independent investigator with a research group dedicated to studying the developmental programs of renal progenitors and the application of this understanding to the origins and prevention/treatment of renal birth defects in humans. PUBLIC HEALTH RELEVANCE: Knowledge of how the kidney develops is paramount to understanding kidney birth defects in humans, which commonly lead to kidney failure. The proposed research will determine how nephrons, the functional unit of the kidney, are properly formed during development. The understanding of this process has the potential to guide generation of therapies for kidney malformations and to prevent kidney disease.